Recent advances have highlighted the ability of hematopoietic stem and progenitor cells in the bone marrow to sense peripheral inflammation or infection and adapt through increased proliferation and ...skewing toward the myeloid lineage. Such adaptations can meet the increased demand for innate immune cells and can be beneficial in response to infection or myeloablation. However, the inflammation-induced adaptation of hematopoietic and myeloid progenitor cells toward enhanced myelopoiesis might also perpetuate inflammation in chronic inflammatory or cardio-metabolic diseases by generating a feed-forward loop between inflammation-adapted hematopoietic progenitor cells and the inflammatory disorder. Sustained adaptive responses of progenitor cells in the bone marrow can also contribute to trained immunity, a non-specific memory of earlier encounters that in turn facilitates the heightened response of these cells, as well as that of their progeny, to future challenges. Here we discuss the mechanisms that govern the adaptation of hematopoietic progenitor cells to inflammation and its sequelae in the pathogenesis of human disease.
Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral process to resolution of ...inflammation is the phagocytosis of dying cells by macrophages, known as efferocytosis. This function is mediated by a complex and well-orchestrated network of interactions amongst specialized phagocytic receptors, bridging molecules, as well as "find-me" and "eat-me" signals. Efferocytosis serves not only as a waste disposal mechanism (clearance of the apoptotic cells) but also promotes a pro-resolving phenotype in efferocytic macrophages and thereby termination of inflammation. Alterations in cellular metabolism are critical for shaping the phenotype and function of efferocytic macrophages, thus, representing an important determinant of macrophage plasticity. Impaired efferocytosis can result in inflammation-associated pathologies or autoimmunity. The present mini review summarizes current knowledge regarding the mechanisms regulating macrophage efferocytosis during clearance of inflammation.
Recent advances indicate that periodontitis is driven by reciprocally reinforced interactions between a dysbiotic microbiome and dysregulated inflammation. Inflammation is not only a consequence of ...dysbiosis but, via mediating tissue dysfunction and damage, fuels further growth of selectively dysbiotic communities of bacteria (inflammophiles), thereby generating a self‐sustained feed‐forward loop that perpetuates the disease. These considerations provide a strong rationale for developing adjunctive host‐modulation therapies for the treatment of periodontitis. Such host‐modulation approaches aim to inhibit harmful inflammation and promote its resolution or to interfere directly with downstream effectors of connective tissue and bone destruction. This paper reviews diverse strategies targeted to modulate the host periodontal response and discusses their mechanisms of action, perceived safety, and potential for clinical application.
The role of neutrophils in trained immunity Kalafati, Lydia; Hatzioannou, Aikaterini; Hajishengallis, George ...
Immunological reviews,
March 2023, Letnik:
314, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone marrow (BM) progenitors ...(central trained immunity) and their innate immune cell progeny, thereby triggering elevated responsiveness against secondary stimuli. BM progenitors can respond to microbial and sterile signals, thereby possibly acquiring trained immunity‐mediated long‐lasting alterations that may shape the fate and function of their progeny, for example, neutrophils. Neutrophils, the most abundant innate immune cell population, are produced in the BM from committed progenitor cells in a process designated granulopoiesis. Neutrophils are the first responders against infectious or inflammatory challenges and have versatile functions in immunity. Together with other innate immune cells, neutrophils are effectors of peripheral trained immunity. However, given the short lifetime of neutrophils, their ability to acquire immunological memory may lie in the central training of their BM progenitors resulting in generation of reprogrammed, that is, “trained”, neutrophils. Although trained immunity may have beneficial effects in infection or cancer, it may also mediate detrimental outcomes in chronic inflammation. Here, we review the emerging research area of trained immunity with a particular emphasis on the role of neutrophils and granulopoiesis.
Eur J Clin Invest 2012; 42 (6): 686–691
Background The process of extravasation of leucocytes from the vasculature into an infected, inflamed or injured tissue, designated the leucocyte adhesion ...cascade, is a major process in innate and adaptive immunity. In every immune process, both agonists and inhibitors, that is, positive and negative regulators, exist.
Materials and methods It was only recently that endogenous inhibitors of the leucocyte adhesion cascade were identified, whereas many selectin, integrin and immunoglobulin superfamily adhesion receptors as well as chemokines and chemokine receptors promoting leucocyte recruitment have been described over the last three decades. Endogenous negative regulators include for instance pentraxin‐3 (PTX‐3) that blocks selectin‐dependent leucocyte rolling, or the endothelium‐derived developmental endothelial locus‐1 (Del‐1) that antagonizes beta2‐integrin‐mediated firm adhesion of leucocytes to the endothelium.
Conclusions As leucocyte infiltration is a major therapeutic target in inflammatory and autoimmune disease, it becomes obvious that such endogenous anti‐adhesive and anti‐inflammatory agents may represent an attractive novel therapeutic platform for inflammatory and immune disorders. This review focuses on these novel endogenous inhibitors of leucocyte recruitment.
Integrins constitute a large group of adhesion receptors that are formed as heterodimers of α and β subunits. Their presence and activation status on the surface of leukocytes modulate a broad ...spectrum of processes in inflammation and immunity. This mini review critically outlines research advances with regard to the function of leukocyte integrins in regulating and integrating the onset and resolution of acute inflammation. Specifically, we summarize and discuss relevant, current literature that supports the multifunctional role of integrins and their partners. The latter include molecules that physically associate with integrins or regulate their activity in the context of the following: 1) leukocyte recruitment to an inflamed tissue, 2) recognition and phagocytosis of apoptotic neutrophils (efferocytosis), and 3) egress of efferocytic macrophages from the inflamed site to lymphoid tissues. The understanding of the fine-tuning mechanisms of the aforementioned processes by integrins and their functional partners may enable the design of therapeutic tools to counteract destructive inflammation and promote more efficient resolution of inflammation.
Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been ...termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that ...maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.
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•Experimental periodontitis (EP) induces maladaptive trained myelopoiesis•EP-induced trained phenotype is transmissible by bone marrow transplantation•IL-1 signaling in hematopoietic progenitors mediates maladaptive training by EP•Maladaptively trained myelopoiesis links the periodontitis-arthritis comorbidity
Trained innate immune responses contribute to pathology of a comorbid condition, as seen with arthritis after periodontitis in animal models.
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